Frontotemporal lobar degeneration represents 10-20% of all dementias and is clinically important because of its earlier age of onset compared to Alzheimer's disease (AD), and its dramatic impact on core human qualities including personality, insight and verbal communication. We recently found that loss-of- function mutations in the gene encoding the secreted growth factor progranulin (PGRN) are an important cause of the most common pathological subtype of FTLD, characterized by neuronal inclusions composed of ubiquitinated TAR DNA-binding protein 43 (TDP43) (FTLD-U). Our working hypothesis is that mutations in PGRN are a more frequent cause of FTLD then initially anticipated and that subtle deregulation of PGRN expression may increase the susceptibility to develop FTLD and a wider range of neurodegenerative diseases. The identification of TDP43 as the pathological protein, not only in FTLD-U, but also in patients with amyotrophic lateral sclerosis (ALS) and in 20-30% of pathologically confirmed AD patients, supports a unifying disease mechanism underlying these disorders. The specific aims of this project are to: 1. Identify the complete spectrum and frequency of mutations in PGRN. In the largest collection of FTLD patients worldwide, we will perform a standardized in- depth mutation screening of PGRN, supplemented with in-vitro functional analyses to determine the disease significance of novel mutations. 2. Identify regulatory cis-acting variants in PGRN that modify disease risk, penetrance or presentation in TDP43 proteinopathies. We will perform genetic association studies of PGRN in FTLD, ALS and AD case-control populations and assess the effect of common PGRN genetic variability on gene expression. 3. Determine the role of miR-659 expression and genetic variability in the development of FTLD. We recently made significant progress in the understanding of the regulation of PGRN when we identified that its expression can be regulated by a specific micro RNA, miR-659. Moreover, we have generated preliminary data suggesting that the common genetic variant rs5848, located in the 3'UTR of PGRN in a predicted binding-site for miR-659, is a major risk factor for FTLD-U through the augmented suppression of PGRN by miR-659. We will perform genetic and expression analyses to determine if deregulation of miR-659 expression in brain or altered genetic variability in the gene encoding miR-659 may contribute directly to the pathogenesis of FTLD-U The proposed studies are relevant to fully appreciate the contribution of PGRN mutations in FTLD leading to increased diagnostic accuracy and counseling. Unveiling the genetic and molecular pathways regulating PGRN may also reveal novel targets that can be exploited for therapeutic actions aimed at delaying the neurodegenerative disease process. PUBLIC HEALTH RELEVANCE: This proposal is designed to define the complete PGRN mutational spectrum in FTLD and to determine whether subtle deregulation of PGRN expression may hold susceptibility to a wider range of neurodegenerative diseases. These studies are relevant to fully appreciate the contribution of PGRN mutations in FTLD leading to increased diagnostic accuracy and counseling. Unveiling the genetic and molecular pathways regulating PGRN may also reveal novel therapeutic targets that can be exploited for therapeutic actions aimed at delaying the neurodegenerative disease process.